Prolactin (PRL) is a neuroendocrine pituitary hormone that is essential for lactogenesis in mammals. The prolactin receptor (PRLR) is a type I transmembrane protein that belongs to the cytokine hematopoeitic receptor superfamily. Both PRL and PRLR play essential roles in breast development and lactation during pregnancy. PRL is produced primarily in the pituitary gland during pregnancy, and interacts with PRLR molecules on mammary epithelial cells in the breast to cause cell proliferation and differentiation during pregnancy. In addition to its primary role in breast development and lactation during pregnancy, it has been postulated that this hormone/receptor pair has additional physiological roles, including regulation of certain aspects of the immune system. Indeed, PRL has been found to be expressed from extrapituitary sources such as the placenta, the normal breast and certain immune cells.
PRL and PRLR have a long-suspected role in breast cancer for several reasons. First, PRL over-expression in mouse models causes mammary tumorigenesis. Second, administration of human PRL to several human breast cancer cells in vitro stimulates their proliferation. Third, a large epidemiological study has shown that there is a positive correlation in women between their circulating serum PRL levels and risk for developing breast cancer (Hankinson et al., J. Natl. Cancer Inst. 91(7):629-34 (1999)). Lastly, several reports indicate that both PRL and PRLR are over-expressed in a high percentage of breast cancer specimens.
At the molecular level, PRL exerts its effects on cells by binding to the PRLR, leading to receptor dimerization and intracellular signaling. PRLR dimerization leads to activation of the receptor via phosphorylation of certain tyrosine residues in the cytoplasmic tail of the receptor. This in turn leads to signaling and activation of the JAK/STAT and Ras pathways. Hyperactivation of Ras signaling is a common feature in a wide variety of human cancers and is known to stimulate cell proliferation and cell survival. Thus, there is strong molecular evidence for a role of PRL signaling in breast cancer, and inhibition of this signaling to MAPK and AKT would be expected to have therapeutic benefit.
The discovery that PRLR and PRL expression is upregulated in a high percentage of breast cancers and/or certain breast cancer cell lines has led to the proposal that inhibition of PRL signaling through its receptor in breast cancers could be therapeutically useful to breast cancer patients. Accordingly, several therapeutic strategies have been developed to inhibit signaling, such as the development of PRL antagonists. One such antagonist is the mutant PRL G129R, which has been shown to inhibit PRL signaling and cause apoptosis in human breast cancer cell lines in vitro. G129R also inhibits breast tumor growth in mouse xenograft models in vivo (Chen et al., Int. J. Oncol. 20:813-818 (2002); Chen et al., Clin. Cancer Res. 5:3583-3593 (1999)). Therefore, the PRL-PRLR signaling pathway is a potential target for breast cancer therapy development.